Indane or dihydroindole derivatives

ABSTRACT

The present invention relates to substituted indane or dihydroindole compounds ofFormula (I),wherein A and B are independently O or S; D is an optionally substituted methylene group; X is N or optionally substituted C; and W is a spacer group. The compounds are either selective dopamine D4 ligands or they have combined effects at dopamine D4 and serotonergic receptors and/or the serotonergic transporter. These compounds are therefore useful in the treatment of certain psychiatric and neurologic disorders, including psychosis, depression and anxiety.

This is a division of application Ser. No. 09/331,557, filed Aug. 3,1999 now U.S. Pat. No. 6,331,544, which is a 371 PCT/DK97/00588 filedDec. 19, 1997 . The prior application is hereby incorporated herein byreference, in its entirety.

FIELD OF THE INVENTION

The present invention relates to a novel class of substituted indane ordihydroindole compounds having effects at dopamine D₄ receptors. Thecompounds are either selective dopamine D₄ ligands or they have combinedeffects at dopamine D₄ and serotonergic receptors and/or theserotonergic transporter. These compounds are therefore useful in thetreatment of certain psychiatric and neurologic disorders, includingpsychosis, depression and anxiety.

BACKGROUND OF THE INVENTION

Related compounds are known from WO patents Nos. WO 9421627-A1, WO9421630-A1, WO 94 21626-A1 describing various series of indolyl- orindazolylmethyl piperidine or piperazine derivatives as selectivedopamine D₄ antagonists. No data are given. The compounds are only saidto give K_(i) values of less than 1.5 μM in a test for displacement of3H spiperone from human dopamine D₄ receptor subtypes in clonal celllines.

EP patent No. 574313 A1 describes compounds with piperidine,tetrahydropyridine, or piperazine rings substituted in position 1 and 4with various aryl or heteroaryl groups, including certain 1-(indane orindanemethyl)piperidine, tetrahydropyridine, or piperazine derivatessubstituted in the 4-position with 1,4-benzodioxane. The compounds areclaimed to have effects at dopamine D₂ and D₄ receptors.

Dopamine D₄ receptors belong to the dopamine D₂ receptor familyconsidered to be responsible for antipsychotic effects of neuroleptics.Furthermore, dopamine D₄ receptors are primarily located in areas of thebrain other than striatum (Van Tol, et al. Nature, 1991, 350, 610), thelow level in striatum suggesting lack of extrapyramidal activity. Also,dopamine D₄ receptor levels have been reported to be elevated inschizophrenic patients (Seeman et al., Nature, 1993, 365, 441.) and theantipsychotic clozapine which is lacking extrapyramidal side effects,has a high affinity for dopamine D₄ receptors (Van Tol, et al. Nature,1991, 350, 610.)

Various effects are known with respect to compounds which are ligands atthe different serotonin receptor subtypes. As regards the 5-HT_(2A)receptor which was previously referred to as the 5-HT₂ receptor, thefollowing effects have e.g. been reported:

Antidepressive effect, improvement of the sleep quality (Meert, T. F.;Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.) and the negativesymptoms of schizophrenia and reduction of extrapyramidal side-effectscaused by treatment with classical neuroleptics in schizophrenicpatients (Gelders, Y. G., British J. Psychiatry, 1989, 155 (suppl. 5,33). Finally, selective 5-HT_(2A) antagonists could be effective in theprophylaxis and treatment of migraine (Scrip Report; “Migraine—Currenttrends in research and treatment”; PJB Publications Ltd.; May 1991).

Clinical studies have shown that 5-HT_(1A) partial agonists are usefulin the treatment of anxiety disorders such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder (Glitz, D.A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate thatalso full agonists are useful in the treatment of the above mentionedanxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6,853).

There is also evidence, both clinical and preclinical, in support of thebeneficial effect of 5-HT_(1A) partial agonists in the treatment ofdepression, impulse control disorders and alcohol abuse (van Hest,Psychopharmacol., 1992, 107, 474; Schipper et al, HumanPsychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158,53; Glitz and Poh, Drugs 1991, 41, 11; Grofet al., Int. Clin.Psychopharmacol. 1993, 8, 167-172; Ansseau et al, Human Psychopharmacol.1993, 8, 279-283).

5-HT_(1A) agonists and partial agonists inhibit isolation inducedaggression in male mice indicating that these compounds are useful inthe treatment of aggression (Sanchez et al., Psychopharmacology, 1993,110, 53-59).

Furthermore, 5-HT_(1A) ligands have been reported to show antipsychoticeffect in animal models (Wadenberg and Ahlenius, J. Neural. Transm.,1991t 83, 43; Ahlenius, Pharmacol. & Toxicol., 1989, 64, 3; Lowe et al.,J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32,1147; and Martin et al., J. Med. Chem., 1989, 32, 1052).

Recent studies also indicate that 5-HT_(1A) receptors are important inthe serotonergic modulation of haloperidol-induced catalepsy (Hicks,Life Science 1990, 47, 1609, Wadenberg et al. Pharmacol. Biochem. &Behav. 1994, 47, 509-513) suggesting that 5-HT_(1A) agonists are usefulin the treatment of EPS induced by conventional antipsychotic agentssuch as haloperidol.

5-HT_(1A) agonists have shown neuroprotective properties in rodentmodels of focal and global cerebral ischaemia and may, therefore, beuseful in the treatment of ischaemic disease states (Prehn , Eur. J.Pharm. 1991, 203, 213).

Pharmacological studies have been presented indicating that 5-HT_(1A)antagonists are useful in the treatment of senile dementia (Bowen et al,Trends Neur. Sci. 1992, 15, 84).

5-HT reuptake inhibitors are well known antidepressant drugs.

Accordingly, dopamine D₄ receptor ligands are potential drugs for thetreatment of psychosis and positive symptoms of schizophrenia andcompounds with combined effects at dopamine D₄ and serotonergicreceptors may have the further benefit of improved effects on otherpsychiatric symptoms in schizophrenic patients such as depressive andanxiety symptoms. As 5-HT_(1A) and 5-HT_(2A) receptor ligand classes ofcompounds and 5-HT reuptake inhibitors have different activities indifferent animal models predictive of anxiolytic and antiaggressiveeffects (Perregaard et al., Recent Developments in Anxiolytics. CurrentOpinion in Therapeutic Patents 1993, 1, 101-128) and/or in modelspredictive of effects in other psychic disorders it might also be highlybeneficial to have such combined serotonergic effects.

SUMMARY OF THE INVENTION

The object of the invention is to provide compounds with dopamine D₄activities or with combined effects at dopamine D₄ receptors andserotonergic receptors and/or the serotonergic transporter.

It has now been found that certain substituted indane or dihydroindolecompounds have effects at dopamine D₄ receptors. Additionally, many ofthe compounds interact with central serotonergic receptors, inparticular with the 5-HT_(1A) and/or the 5-HT_(2A) receptors and/or theyact as 5-HT reuptake inhibitors.

Accordingly, the present invention relates to novel compounds of theformula I.

wherein A and B are independently O or S;

D is a methylene group optionally substituted with one or two C₁₋₄ alkylgroups;

Y is a hydrocarbon group completing an indane ring, a group NR¹completing a dihydroindole ring, or a group N completing a dihydroindolering attached via the 1-position;

W is a bond, and n+m is 1, 2, 3, 4, 5, or 6;

W is CO, SO, or SO₂, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, providedthat n+m is not more than 6; or

W is O, S, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+mis not more than 6, and

provided that when Y is N completing a dihydroindole ring attached viathe 1-position then m is 2, or 3; and when Y is NR¹ completing adihydroindole ring linked via the 2-position then m is 1, 2, or 3;

the dotted line, emanating from X, indicates an optional bond; when itdoes not indicate a bond X is N, CH or COH; and when it indicates a bondX is C;

R¹ is selected from

hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalk(en)yl,C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, aryl, heteroaryl, aryl-C₁₋₆alkyl, heteroaryl-C₁₋₆ alkyl, acyl, thioacyl, C₁₋₆ alkylsulfonyl,trifluoromethylsulfonyl, arylsulfonyl or heteroarylsulfonyl, or

R¹⁵VCO— wherein V is O or S and R¹⁵ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl, or

a group R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— wherein R¹⁶ and R¹⁷ are independentlyhydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, arylor heteroaryl, or R¹⁶ and R¹⁷ together with the N-atom to which they arelinked, form a pyrrolidinyl, piperidinyl or perhydroazepin group;

R²-R⁵ are independently selected from hydrogen, halogen, cyano, nitro,C₁₋₆ alk(en/yn)yl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxy, C₃₋₈cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, C₁₋₆alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl,trifluoromethyl, trifluoromethylsulfonyloxy and C₁₋₆ alkylsulfonyl, oneof R²-R⁵ alternatively being a group —NR¹³R¹⁴ wherein R¹³ is selectedfrom the R¹ substituents; R¹⁴ is hydrogen, C₁₋₆ alkyl, C₂₋₆, alkenyl,C₂₋₆, alkynyl, C₃₋₈ cycloalk(en)yl, C₃₋₈, cycloalk(en)yl-C₁₋₆alk(en/yn)yl, aryl, heteroaryl, aryl-C₁₋₆ alkyl or heteroaryl-C₁₋₆alkyl, or R¹³ and R¹⁴ together with the N-atom to which they are linkedform a group

wherein Q is C═O, C═S or CH₂; T is NH, S, O or CH₂; and p is 1-4,inclusive;

or two adjacent groups taken from R² -R⁵ may be joined and designate a—(CH₂)₃— or —CH═CH—NH— thereby forming a fused 5-membered ring;

R⁶-R⁸ are independently hydrogen, halogen, cyano, nitro,C₁₋₆-alk(en/yn)yl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, or C₁₋₆ alkylsulfonyl;

with the proviso that the substituent R³ or R⁴ in 6-position may not be—NR¹³R¹⁴ when Y is CH₂ and the ring is linked via the 1-position; andpharmaceutically acceptable acid addition salts thereof.

The compounds of the invention have been found to show high affinity fordopamine D₄ receptors and some of the compounds were found also to showaffinity for serotonergic receptors including 5-HT_(1A) receptors and/orfor 5-HT_(2A) receptors. In addition to the effects at these receptorsubtypes, certain of the present compounds also show 5-HT reuptakeinhibiting effect.

Accordingly, the compounds of the invention are considered useful in thetreatment of positive and negative symptoms of schizophrenia, otherpsychoses, anxiety disorders, such as generalised anxiety disorder,panic disorder, and obsessive compulsive disorder, depression, alcoholabuse, impulse control disorders, aggression, side effects induced byconventional antipsychotic agents, ischaemic disease states, migraine,senile dementia and cardiovascular disorders and in the improvement ofsleep.

In another aspect the invention provides a pharmaceutical compositioncomprising at least one compound of Formula I as defined above or apharmaceutically acceptable acid addition salt thereof or prodrugthereof in a therapeutically effective amount and in combination withone or more pharmaceutically acceptable carriers or diluents.

In a further aspect the present invention provides the use of a compoundof Formula I as defined above or an acid addition salt or prodrugthereof for the manufacture of a pharmaceutical preparation for thetreatment of the above mentioned disorders.

DETAILED DESCRIPTION OF THE INVENTION

Some of the compounds of general Formula I exist as optical isomersthereof and such optical isomers are also embraced by the invention.

Prodrugs of the compounds of general Formula I are also embraced by theinvention.

The expression C₁₋₆-alk(enlyn)yl means that the group may be anC₁₋₆-alkyl, C₂₋₆-alkenyl, or C₁₋₆-alkynyl group.

The expression C₃₋₈-cycloalk(en)yl means a C₃₋₈-cycloalkyl group, or aC₃₋₈-cycloalkenyl group.

The term C₁₋₆ alkyl refers to a branched or unbranched alkyl grouphaving from one to six carbon atoms inclusive, such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and2-methyl-1-propyl.

Similarly, C₂₋₆ alkenyl and C₂₋₆ alkynyl, respectively, designate suchgroups having from two to six carbon atoms, inclusive. Preferred groupsare those having from two to four carbon atoms.

The terms C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylamino, C₁₋₆ alkylcarbonyl, etc. designate such groups in which thealkyl group is C₁₋₆ alkyl as defined above.

The term C₃₋₈ cycloalkyl designates a monocyclic or bicyclic carbocyclehaving three to eight C-atoms, such as cyclopropyl, cyclopentyl,cyclohexyl, etc.

The term C₃₋₈ cycloalkenyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms and containing a double bond.

The term aryl refers to a mono- or bicyclic carbocyclic aromatic group,such as phenyl, and naphthyl, in particular phenyl.

The term heteroaryl refers to a mono- or bicyclic heterocyclic aromaticgroup, such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl,pyridyl, and furanyl, in particular pyrimidyl, indolyl, and thienyl.

Halogen means fluoro, chloro, bromo or iodo.

As used herein the term acyl refers to a formyl, C₁₋₆alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C₁₋₆ alk(en/yn)ylcarbonyl,cycloalkylcarbonyl, or cycloalkyl-C₁₋₆ alk(en/yn)ylcarbonyl group andthe term thioacyl is the corresponding acyl group in which the carbonylgroup is replaced with a thiocarbonyl group.

The expression alk(en/yn)yl means that the group may be an alkyl,alkenyl, or alkynyl group.

As indicated in Formula I, the Y comprising ring may have a variableattachment point. Thus it may be linked to the W—(CH₂)_(n) group via the1- or 2-position when Y is hydrocarbon or the 1-, 2- or 3-position whenY is NR¹.

In Formula I, X is preferably —C═ or —CH— and Y is preferablyhydrocarbon or NR¹ wherein R¹ is hydrogen, C₁₋₆ alkyl, or C₁₋₆alkylcarbonyl. Most preferably Y is CH₂ and in that case the indane ringis preferably linked via the 1-position.

W is preferably a bond and n+m is preferably 1-4, in particular 1 or 2.

R¹ is preferably hydrogen, methyl or acetyl most preferably hydrogen.

Each of R²-R⁵ is preferably hydrogen, halogen, cyano or one of them agroup NR¹³R¹⁴ wherein R¹³ is acyl, C₁₋₆ alkyl, C₁₋₆ alkoxy or a groupR¹⁶R¹⁷NCO wherein R¹⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl and R¹⁷ is hydrogen or loweralkyl or R¹⁶ and R¹⁷ together with the N-atom to which they are linked,form a pyrrolidinyl, piperidinyl or perhydroazepin group. Morepreferably, R¹³ is formyl, acetyl, methylaminocarbonyl,methylaminothiocarbonyl, dimethylaminocarbonyl,dimethylaminothiocarbonyl, methylsulfonyl, aminocarbonyl, cyclopropylcarbonyl, methyl, pyrrolidinylcarbonyl or4-fluorophenylaminocarbonyl and R¹⁴ is preferably hydrogen or loweralkyl, most preferably hydrogen or methyl, or R¹³ and R¹⁴ are linkedtogether to form a 5-7 membered unsubstituted lactam ring or apyrrolidinyl, piperidinyl or perhydroazepin.

R⁶ to R⁸ are preferably selected from hydrogen, halogen, cyano, nitro,C₁₋₆-alk(en/yn)yl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, or C₁₋₆ alkylsulfonyl. More preferred R⁶ to R⁸ areselected from hydrogen, halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy.

A and B are preferably both O.

D is preferably methylene or methylene substituted with methyl, dimethylformyl or acetyl.

A preferred subclass of compounds are those wherein Y is CH₂ theresulting indane ring being linked via the 2-position, A and B are bothO and D is optionally substituted methylene.

In another subclass of compounds Y is CH₂ the resulting indane ringbeing linked via the 1-position, A and B are both O and D is optionallysubstituted methylene.

In another subclass of compounds Y is NR¹ the dihydroindole ring beinglinked via the 3-or 1-position, preferably the 3-position, A and B areboth O and D is optionally substituted methylene.

In a further subclass of compounds are those wherein W is a bond.

Another subclass of compounds of the invention are those wherein one ofR²-R⁵ is a group —NR¹³R¹⁴.

In yet another subclass of compounds of the invention neither of R²-R⁵is a group —NR¹³R¹⁴.

In yet another subclass of compounds of the invention X is N.

In a last subgroup of compounds of the invention at least one of A and Bis S.

The acid addition salts of the invention are pharmaceutically acceptablesalts of the compounds of Formula I formed with non-toxic acids.Exemplary of such organic salts are those with maleic, fumaric, benzoic,ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, and nitric acids. The pharmaceutical compositionsof this invention or those which are manufactured in accordance withthis invention may be administered by any suitable route, for exampleorally in the form of tablets, capsules, powders, syrups, etc., orparenterally in the form of solutions for injection. For preparing suchcompositions, methods well known in the art may be used, and anypharmaceutically acceptable carriers, diluents, excipients, or otheradditives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unitdosage form containing said compounds in an amount of about 0.01 to 100mg. The total daily dose is usually in the range of about 0.05-500 mg,and most preferably about 0.1 to 50 mg of the active compound of theinvention.

The compounds of the invention may be prepared as follows:

a) alkylating a piperazine, piperidine, or tetrahydropyridine of theformula II with an alkylating derivative of the formula III:

wherein R²-R⁸, X, Y, A, B, D, n, m, W, and the dotted line are aspreviously defined, and L is a leaving group such as eg. halogen,mesylate, or tosylate; or

b) reducing the amide carbonyl in a compound of the following FormulaIV:

wherein R²R⁸, X, Y, A, B, D, m, W and the dotted line are as previouslydefined and n is 1, 2, 3, 4 or 5; or

c) introducing a substituent R²′, R³′, R⁴′ or R⁵′ by reacting a compoundof the following Formula V:

wherein one of R²′-R⁵′ is hydrogen and the others are the correspondingR², R³, R⁴, or R⁵ as previously defined and R⁶-R⁸, X, Y, A, B, D, m, n,W, and the dotted line are as previously defined, by using a reactivereagent such as a halogen or a halogenating agent, a sulfonating agent,a nitration agent or a reactive agent generating carbonium ions (RCO⁺,R⁺) wherein R is alkyl alkynyl, aryl cycloalkyl, heteroaryl cycloalkyl,or cycloalk(en/yn)yl; or

d) reducing the double bond in an indole compound of the followingFormula VI:

wherein R¹, R²-R⁸, A, B, C, X, n, m and W are as previously defined; or

e) reducing the tetrahydropyridinyl double bond in derivatives of thefollowing Formula VII:

wherein R²-R⁸, Y, n, m, W, A, B and D are as previously defined; or

f) Reacting a dihydroindole derivative of formula VIII:

wherein R²-R⁸, X, A, B, D, n, m, W, and the dotted line are aspreviously defined, with a reagent of the formula R¹—L, where L is aleaving group such as halogen, mesylate or tosylate and R¹ is aspreviously defined, or of the formula R¹′-hal or R¹′—OCOR, in whichformulas hal is halogen, R¹′ is acyl, thioacyl, a group R¹⁵VCO—, or agroup R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— where R¹⁵, V, R¹⁶ and R¹⁷ are aspreviously defined except that neither R¹⁶ nor R¹⁷ may be hydrogen, orwith a lower alkylsulfonyl halogenide, trifluoromethylsulhonylhalogenide or an isocyanate or thioisocyanate of the formula R¹⁶—N═C═Oor R¹⁶—N═C═S wherein R¹⁶ is as previously defined;

g) reacting an anilino derivative of the formula IX:

wherein one of R²-R⁵ is NHR¹⁴, and R¹⁴ is defined as above and the otherR²-R⁸, X, Y, A, B, D, n, m, W, and the dotted line are as previouslydefined, with a reagent of the formula R¹³—L, where L is a leaving groupsuch as halogen, mesylate or tosylate and R¹³ is as previously defined,or of the formula R¹³′-hal or R¹³′—OCOR, in which formulas hal ishalogen, R¹³′ is acyl, thioacyl, a group R¹⁵VCO—, or a group R¹⁶R¹⁷NCO—or R¹⁶R¹⁷NCS— where R¹⁵, V, R¹⁶ and R¹⁷ are as previously defined exceptthat neither R¹⁶ nor R¹⁷ may be hydrogen, or with a lower alkylsulfonylhalogenide, trifluoromethylsulhonyl halogenide or an isocyanate orthioisocyanate of the formula R¹⁶—N═C═O or R¹⁶—N═C═S wherein R¹⁶ is aspreviously defined,

h) Alkylating a dihydroindole derivative of the Formula X with analkylating derivative of the Formula XI:

wherein R²-R⁸, X, Y, A, n, m, W, and the dotted line are as previouslydefined, and L is a leaving group such as eg. halogen, mesylate, ortosylate; or

i) reducing the carbonyl amide compounds of Formula XII:

wherein R² -R⁸, X, Y, A, n, W and the dotted line are as previouslydefined and m is 1, 2, 3, 4 or 5; whereupon the compound of Formula I isisolated as the free base or a pharmaceutically acceptable acid additionsalt thereof.

The reaction in Methods f) and g) are conveniently performed at lowtemperature (eg. below room temperature) in an inert solvent such asacetone, dichloromethane, tetrahydrofuran or dimethoxyethane whenreactive carboxylic acid chlorides, isocyanates, or isothiocyanates areused. Formylated amines are prepared from the corresponding amines byreaction in formic acid, with esters of formic acid, or by reaction withmixed formic acid anhydride prepared in situ. Generally reactiontemperatures are between 0° C. and the boiling point of the formnylprecursor compounds.

The alkylations according to Methods a) and h) are generally performedby refluxing in a suitable solvent such as acetone, methyl isobutylketone, tetrahydrofuran, dioxane, ethanol or 2-propanol in the presenceof a base such as triethylamine or potassium carbonate.

The reductions of double bonds according to Methods d) and e) aregenerally performed by catalytic hydrogenation at low pressure (<3 atm.)in a Parr apparatus, or by using reducing agents such as diborane orhydroboric derivatives as produced in situ from NaBH₄ in trifluoroaceticacid in inert solvents such as tetrahydrofuran, dioxane, or diethylether.

The reductions according to Method b) and i) are generally performed byuse of LiAlH₄, AlH₃ or diborane in an inert solvent such astetrahydrofuran, dioxane, or diethyl ether at room temperature or at aslightly elevated temperature.

The halogenation according to Method c) is generally performed by use ofchlorine, bromine, or N-chlorosuccinimide, N-bromosuccinimide or anotherhalogen precursor molecule, conveniently in the presence of a catalystsuch as Fe ions or a mineral acid.

Methylene- or ethylenedioxyphenylpiperazine, piperidine andtetrahydropyridyl starting materials are commercially available or maybe prepared by literature procedures.

Key intermediates such as 1-indanecarboxylic acid (V. Asham and W. H.Linnell, J. Chem. Soc. 1954, 4691-4693, Hansen et al. Helv. Chim. Acta1982, 33, 325-343) and 6-nitro-1-indanecarboxylic acid (G. Kirsch et al.Just. Lieb. Ann. Chem. 1976, 10, 1914) were prepared according towell-known literature procedures.

EXPERIMENTAL SECTION

Melting points were determined on a Büichi SMP-20 apparatus and areuncorrected. Mass spectra were obtained on a Quattro MS-MS system fromVG Biotech, Fisons Instruments. The MS-MS system was connected to an HP1050 modular HPLC system. A volume of 20-50 μl of the sample (10 μg/ml)dissolved in a mixture of 1% acetic acid in acetonitril/water 1:1 wasintroduced via the autosampler at a flow of 30 μl/min into theElectrospray Source. Spectra were obtained at two standard sets ofoperating conditions. One set to obtain molecular weight information(MH+) (21 eV) and the other set to induce fragmentation patterns (70eV). The background was subtracted. The relative intensities of the ionsare obtained from the fragmentation pattern. When no intensity isindicated for the Molecular Ion (MH+) this ion was only present underthe first set of operating conditions. 1H NMR spectra were recorded ofall novel compounds at 250 MHz on a Bruker AC 250. Deuterated chloroform(99.8%D) or dimethylsulfoxide (99.9%D) were used as solvents. TMS wasused as internal reference standard. Chemical shift values are expressedin ppm-values. The following abbreviations are used for multiplicity ofNMR signals: s=singlet, d=doublet, t=tiplet, q=quartet, qui=quintet,h=heptet, dd=double doublet, dt=double triplet, dq=double quartet,tt=triplet of triplets, m=multiplet. NMR signals corresponding to acidicprotons are generally omitted. Content of water in crystalline compoundswas determined by Karl Fischer titration. Standard workup proceduresrefer to extraction with the indicated organic solvent from properaqueous solutions, drying of combined organic extracts (anhydrous MgSO₄or Na₂SO₄), filtering and evaporation of the solvent in vacuo. Forcolumn chromatography silica gel of type Kieselgel 60, 230-400 mesh ASTMwas used.

EXAMPLE 1 1-Indanylmethanol, 1a

To a suspension of LiAlH₄ (4.7 g) in diethyl ether (200 ml) was addeddropwise a solution of AlCl₃ in diethyl ether (200 ml). A solution of1-indanecarboxylic acid (10 g) (prepared according to the method ofHansen et al. Helv. Chim. Acta 1982, 33, 325-343) in dry tetrahydrofuran(200 ml) was added dropwise at 10-15° C. The mixture was finally stirredat room temperature for 1.5 hours. Excess AlH₃ was destroyed by additionof concentrated aqueous NaOH solution (25 ml) at 0° C. Precipitatedinorganic salts were filtered off and the solvents evaporated in vacuoleaving 6.8 g of the title compound la as a viscous oil which was usedwithout further purification.

The following -indanylmethanols were prepared in a similar manner:6-Bromo-1-indanylmethanol from alane reduction of the correspondingmethyl 6-bromo-1-indanecarboxylic acid ester, isolated as a viscous oil.1b.

EXAMPLE 2 6-Cyano-1-indanylmethanol 2a

To a solution of 6-bromo-1-indanylmethanol (20 g) inN-methyl-2-pyrrolidone (NMP) (380 ml) was added CuCN (79 g). The mixturewas heated at 160° C. for 6 hours. After cooling to 80-90° C. themixture was poured into an aqueous solution (500 ml) of NaCN (4g). Afterstirring for 20 minutes excess CuCN was filtered off. Ethyl acetate (300ml) was added and the organic phase was separated and worked-up. Theremaining oil was dissolved in diethyl ether (300 ml) and washed withsaturated brine (2×100 ml). The organic phase was separated and workedup according to the general procedure leaving 14.6 g of crude titlecompound 2a as a visceous oil. Column chromatography on silica gel(eluent:ethylacetat/heptane 6:4) afforded pure 2a (8.7 g) which was usedwithout further purification.

EXAMPLE 3 6-Cyano-1-indanylmethanol Methanesulfonate, 3a

To a solution of 6-cyano-1-indanylmethanol 2a (3 g) and triethylamine(2.8 ml) in dichloromethane (50 ml) was added dropwise a solution ofmethansulfonylchloride (1.5 ml) in dichloromethane (25 ml) at 0° C. Themixture was stirred at room temperature for 1 hour. Water was added (200ml) and the organic phase was subsequently separated and worked-upaccording to the standard procedure above. The remaining crystallineproduct was stirred with diethyl ether and filtered off. Yield 2.7 g. Mp62-63° C.

The following methanesulfonates were prepared in a similar manner:1-Indanylmethanol methanesulfonate, 3b. Isolated as a viscous oil6-Bromo-1-indanylmethanol methanesulfonate, 3c.

EXAMPLE 4 Method a1-(1-Indanylmethyl-4-(3,4-methylenedioxyphenyl)piperazine, Fumarate, 4a

A mixture of 1-Indanylmethanol methanesulfonate, 3b (5.8 g) and1-(3,4-methylene-dioxyphenyl)piperazine (commercially available) (11 g)in NMP (100 ml) was heated at 110° C. for 5 hours. After cooling to roomtemperature the mixture was poured into diluted aqueous NH₄OH.Extraction with a 1:1 mixture of diethyl ether/ethyl acetate (3×100 ml)afforded 13.1 g of a very impure product. Purification by columnchromatography on silica gel (eluted with heptane/ethylacetate/triethylamine 80/20/4) yielded pure title compound (2.7) whichprecipitated as the fuimarate salt 4a from ethanol. Mp>311° C. ¹H NMR(DMSO-d₆): d 1.70-1.90 (m, 1H); 2.15-2.30 (m, 1H); 2.45 (dd, 1H); 2.65(broad t, 4H); 2.55-2.70 (m, 2H); 2.70-2.95 (m, 2H); 3.05 (broad t, 4H);3.35 (quin, 1H); 5.85 (s, 2H); 6.45 (dd, 1H); 6.65 (s, 2H); 6.70 (d,1H); 6.75 (d, 1H); 7.15-7.30 (m, 3H); 7.35 (dd, 1H); MS m/z (%): 337(MH+, 62%), 207 (24%), 131 (100%).

In a similar way the following compound was prepared:

1-(6-Bromo-1-indanylmethyl-4-(3,4-methylenedioxyphenyl)piperazine,Fumarate, 4b

mp 158-161° C. ¹H NMR (DMSO-d₆): d 1.65-1.80 (m, 1H); 2.10-2.25 (m, 1H);2.40 (dd, 1H); 2.60 (broad t, 4H); 2.50-2.60 (m, 2H); 2.65-2.90 (m, 2H);3.05 (broad t, 4H); 3.40 (quin, 1H); 5.95 (s, 2H); 6.35 (dd, 1H); 6.65(s, 2H); 6.70 (d, 1H); 6.75 (d, 1H); 7.15 (d, 1H); 7.25 (dd, 1H); 7.55(d,1H). MS m/z (%): 417 (35%), 415 (MH+, 35%), 219 (30%), 209 (32%), 206(30%), 164 (24%), 130 (100%).

EXAMPLE 51-[2-[4-(3,4-Methylenedioxyphenyl)-piperazine-1-yl]methylearbonyl]-indane,5a

A solution of indane-1-acetic acid (Anderson, A. G. et al; J. Org. Chem.1973, 38(8), 1439-1444) (2.5 g, 14.2 mmol), DMF (1 ml) and SOCl₂ (6.2 g,52.5 mmol) in CH₂Cl₂ (100 ml) was refluxed for 4 h. The mixture wasevaporated and re-evaporated from toluene to give the corresponding acidchloride. To a solution of 1-(3,4-methylenedioxyphenyl)-piperazinehydrochloride (6.9 g, 28.4 mmol) and TEA (6 ml) in TBE (70 ml) was addeddropwise over 20 min. a solution of the acid chloride in THE (70 ml).The mixture was stirred for 1 h and evaporated. H₂O (30 ml) was added tothe remanence and the mixture was extracted with CH₂Cl₂ (2×100 ml).After washing with H₂O (10 ml) and brine (10 ml) the combined organicphases were dried with MgSO₄ and evaporated. The product was purified bycolumn chromatography (EtOAc:heptane=1:1) to give the title compound 5a(3.3 g, 64%): 1H NMR (DMSO-d₆) d 1.65-1.82 (1H, m), 2.34-2.54 (2H, m),2.72-2.83 (1H, dd), 2.86-3.07 (6H, m), 3.48-3.59 (2H, m), 3.62-3.76 (1H,m), 3.77-3.82 (2H, m), 5.88 (2H, s), 6.32 (1H, dd), 6.53 (1H, d), 6.70(1H, d), 7.11-7.25 (4H, m).

The following amide was prepared in a similar manner:

2-[4-(3,4-Methylenedioxyphenyl)-piperazine-1-yl]carbonyl]-indane, 5b

mp 114-116° C.

This compound was prepared from indane-2-carboxylic acid which again wasprepared by heating a solution of indane-2,2-dicarboxylic acid (17 g,Baeyer and Perkin, Ber. 1884, 17, 122) in NMP (200 ml) to 150° C. for 1hour. After cooling to 20° C. the solution was poured in water (300 ml)and concentrated hydrochloric acid was added to pH=1. Conventional workup with ether gave indane-2-carboxylic (4.7 g). Mp 132-33° C. (fromether).

EXAMPLE 61-[2-[4-(3,4-Methylenedioxyphenyl)-piperazine-1-yl]ethyl]-indaneFumarate, 6a

To a supension of LiAlH₄ (1.0 g, 27.2 mmol) in THF (70 ml) was addeddropwise over 20 min. a solution of 5a (3.3 g, 9.1 mmol) in THF (70 ml).The mixture was refluxed for 1.5 h and then cooled to 10-15° C. Afterdropwise addition of H₂O (1 ml), aqueous (15%) NaOH (1 ml) and H₂O (5ml), the solution was filtered and evaporated to allmost dryness. Theremanence was dissolved in CH₂Cl₂ and after drying with MgSO₄, thesolution was evaporated to give the free base of 6a, which was dissolvedin acetone (15 ml) and treated with fumaric acid (1.1 g) dissolved inEtOH to give the title compound 6a (2.5 g, 59%): mp 191-192° C., ¹H NMR(DMSO-d₆) d 1.45-1.70 (2H, m), 2.00-2.15 (1H, m), 2.15-2.30 (1H, m),2.50-2.60 (2H, m), 2.65-2.70 (4H, m), 2.70-2.90 (2H, m), 3.00-3.20 (5H,m), 5.90 (1H, s), 6.30 (2H, dd), 6.60 (2H, s), 6.65 (1H, d), 6.70 (1H,d), 7.10-7.30 (4H, m). MS m/z (%): 351 (MH+, 100%), 188 (27%), 117(19%).

The following compound was prepared in a similar way using compound 5bas starting material:

2-[4-(3,4-Methylenedioxyphenyl)-piperazine-1-yl]methyl]-indane, Oxalate,6b

mp 197-199° C. ¹H NMR (DMSO-d₆) d 2.70 (dd, 2H), 2.85 (quintet, 1H),2.95-3.35 (m, 12H), 5.95 (s, 2H), 6.40 (dd, 1H), 6.75 (d, 1H), 6.80 (d,1H), 7.10-7.25 (m, 4H). MS m/z (%): 337 (MH+, 100%), 174, (14%),131(26%).

EXAMPLE 71-Acetyl-2,3-dihydro-3-[1-(2-methanesulphonyl)ethyl]-1H-indole, 7a

To a solution of indole-3-acetic acid (100 g) in methanol (1 l) wasadded ether saturated with HCl (200 ml), and the solution was left atroom temperature for 3 hours. The solution as evaporated in vacuo, andthe residue was dissolved in THF 1.2 l) and added slowly with cooling toa stirred suspension of LiAlH₄ (28.6 g) in THF (1 l). After stirring for2 hours at room temperature, the mixture was cooled in an ice bath, andwater (57 ml), 15% NaOH (29 ml), and water (143 ml) was added. Themixture was filtered and evaporated in vacuo, and the residue (84.9 g)was dissolved in dioxane (1.5 l). Borane trimethylamine complex (200 g)was added, and and to the stirred mixture was added concentratedhydrochloric acid (150 ml) during 1 hour. The mixture was heated to 40°C. for 30 minutes and then to reflux for 2.5 hours. Then 6 Mhydrochloric acid (460 ml) was added and reflux was continued for 30minutes. The solution was concentrated in vacuo, and the residue waspoured on ice. The solution was washed with ether and was made basicwith concentrated NaOH and then extracted with ether. The organic phasewas dried over MgSO₄ and was evaporated in vacua. The residue wasdissolved in CH₂Cl₂ (680 ml) and triethylamine (68 ml). Acetyl chloride(36 ml) was added at 5° C. during 1 hour. After further stirring for 1hour at room temperature, the mixture was washed with dilutehydrochloric acid, and NaHCO₃ solution. After drying over MgSO₄ andevaporation in vacuo, the residue was dissolved in methanol (500 ml),and 30% Na-methanolat (10 ml) was added. The mixture was stirred for 4hours at room temperature and was then evaporated in vacuo and wasdissolved in CH₂Cl₂ and was washed with saturated NaCl solution, driedover MgSO₄ and evaporation in vacuo. The residue (75.4 g) was dissolvedin CH₂Cl₂ (1 l) and triethylamine (100 ml). With cooling was added asolution of methanesulphonic chloride (27 ml) in CH₂Cl₂ (175 ml) at 10°C. After stirring for 30 minutes at 0° C. and 1 hour at roomtemperature, the mixture was evaporated in vacuo and was purified onsilica gel eluted with ethyl acetate to give the title produduct as anoil (74 g).

EXAMPLE 8 1-(4-Chloro-1-oxobtutan-1-yl)-2,3-dihydro-1H-indole, 8a

The title compound was prepared in a similar way as Example 7 using acooled solution of 2,3-dihydro-1H-indole (10 g) in CH₂Cl₂ (125 ml) andtriethylamine (13 ml) by adding 4-chlorobutyryl chloride (10 ml) at lessthan 10° C. Conventional work up gave the title compound as an oil.Yield 16.4 g.

EXAMPLE 92,3-Dihydro-3-[4-[4[(3,4-methylenedioxyphenyl)piperazine-1-yl]butyl-1-oxo]]-1H-indole,Oxalate 9a

A mixture of 3,4-methylenedioxyphenylpiperazine (2.50 g), 8a (2.78 g),and K₂CO₃ (1.85 g) in MIBK (100 ml) was heated to reflux for 16 hours.The mixture was filtrated and evaporated in vacuo, and the residue wasdissolved in ethyl acetate and worked up in a conventional manner togive a crude product (3.5 g) which was purified on silica gel elutedwith ethyl acetate-heptane triethylamine (64:31:5). The title oxalatewas crystallized from acetone. Yield 0.20 g, mp 198-200° C. ¹H NMR(DMSO-d₆) d 1.85-2.00 (m, 2H), 2.55 (t, 2H), 3.00 (t, 2H), 3.05-3.30 (m,8H), 3.50-4.00 (m, 2H), 4.05 (t, 1H), 5.9 (s, 2H), 6.40 (dd, 1H), 6.75(d, 1H), 6.80 (d, 1H), 7.00 (t, 1H), 7.15 (t, 1H), 7.25 (d, 1H), 8.10(d, 1H).

1-Acetyl-2,3-dihydro-3-[2-[4-[(3,4-methylenedioxyphenyl)piperazine-1-yl]ethyl]]1H-indole,9b

From 7a and 3,4-methylenedioxyphenylpiperazine. Mp 185-7° C. 1H NMR(DMSO-d6) d 1.75-2.00 (m, 1H), 2.10-2.25 (m, 1H), 2.15 (s, 3H),2.90-3.15 (m, 2H), 3.2 (d, 8H), 3.35-3.55 (m, 1H), 3.80 (dd, 1H), 4.20(t, 1H), 5.90 (s, 2H), 6.35 (dd, 1H), 6.75 (d, 1H), 6.80 (d, 1H), 7.00(t, 1H), 7.20 (t, 1H), 7.30 (d, 1H), 8.05 (d, 1H). MS m/z (%): 394 (MH+,100%), 219 (3%), 146 (2%).

Pharmacological Testing

The compounds of the invention were tested in well recognized andreliable methods. The tests were as follows:

³H-YM-09151-2 BINDING

By this method the inhibition by drugs of the binding of the dopamine D₄antagonist ³H-YM-09151-2 to dopamine D₄ receptors in cloned humandopamine receptor subtype 4.2 membranes is determined in vitro.Accordingly, this is a test for affinity for dopamine D₄ receptors. Thetest is performed using a preparation of cloned dopamine D₄ cellmembranes CRM-016®, Dupharma A/S, Denmark, in accordance with theproduct specifications. The results are given in the following Table 1as IC₅₀-values.

TABLE 1 Binding Data (IC₅₀ values in nM or % inhibition of binding at 50nM) Comp. No Binding 4a 8.8 4b 33% at 50 nM 6a 5.6 6b 1.8 9a 4.3 9b 3.7

³H-8-OH-DPAT Binding.

By this method the inhibition by drugs of the binding of the 5-HT_(1A)agonist ³H-8-OH-DPAT (1 nM) to 5-HT_(1A) receptors in membranes from ratbrain minus cerebellum is determined in vitro. Accordingly, this is atest for affinity for 5-HT_(1A) receptor. The test is performed asdescribed by Hyttel et al., Drug. Dev. Res., 1988, 15, 389-404.

³H-Ketanserin Binding.

By this method the inhibition by drugs of the binding of ³H-Ketanserin(0,5 nM) to 5-HT_(2A) receptors in membranes from rat is determined invitro. The method is described in Hyttel, Pharmacology & Toxicology, 61,126-129, 1987.

In addition to the above tests, the compounds of the invention weretested with respect to affinity for the dopamine D₂ receptor bydetermining their ability to inhibit the binding of ³H-spiroperidol toD₂ receptors by the method of Hyttel et al, J. Neurochem., 1985, 44,1615. Furthermore, they were tested with respect to their 5-HT reuptakeinhibiting effect by measuring their ability to inhibit the uptake of ³H-serotonin in rat brain synapsomes in vitro by the method descibed byHyttel and Larsen, Acta Pharmacol. Tox., 1985, 56, suppl. 1, 146-153.

In general, the compounds of the invention have been found potently toinhibit the binding of tritiated YM-09151-2 to dopamine D₄ receptors.Furthermore, many of the compounds have been found to inhibit thebinding of tritiated 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) to5-HT_(1A) receptors and/or the binding of ³H ketanserin to 5-HT₂Areceptors in vitro. Some compounds only bind to one of the two serotoninreceptor subtypes, 5-HT_(1A) or 5-HT_(2A). In addition to these affects,a number of the compounds have proven to have the further advantage of apotent 5-HT reuptake inhibiting effect and/or effects at otherserotonergic receptors. The compounds have no substantial or only weakaffinity for the dopamine D₂ receptor.

Accordingly, the compounds of the invention are considered useful in thetreatment of positive and negative symptoms of schizophrenia, otherpsychoses, anxiety disorders, such as generalised anxiety disorder,panic disorder, and obsessive compulsive disorder, depression, alcoholabuse, impulse control disorders aggression, side effects induced byconventional antipsychotic agents, ischaemic disease states, migraine,senile dementia and cardiovascular disorders and in the improvement ofsleep.

FORMULATION EXAMPLES

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art.

For example: Tablets may be prepared by mixing the active ingredientwith ordinary adjuvants and/or diluents and subsequently compressing themixture in a conventional tabletting machine. Examples of adjuvants ordiluents comprise: corn starch, potato starch, talcum, magnesiumstearate, gelatine, lactose, gums, and the like. Any other adjuvants oradditives usually used for such purposes such as colourings,flavourings, preservatives etc. may be used provided that they arecompatible with the active ingredients. Solutions for injections may beprepared by dissolving the active ingredient and possible additives in apart of the solvent for injection, preferably sterile water, adjustingthe solution to desired volume, sterilisation of the solution andfilling in suitable ampules or vials. Any suitable additiveconventionally used in the art may be added, such as tonicity agents,preservatives, antioxidants, etc.

Typical examples of recipes for the formulation of the invention are asfollows:

1) Tablets containing 5.0 mg of Compound 4a calculated as the free base:

Compound 4a 5.0 mg Lactose 60 mg Maize starch 30 mgHydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mgCroscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg

2) Tablets containing 0.5 mg of Compound 6a calculated as the free base:

Compound 6a 0.5 mg Lactose 46.9 mg Maize starch 23.5 mg Povidone 1.8 mgMicrocrystalline cellulose 14.4 mg Croscarmellose Sodium Type A 1.8 mgMagnesium stearate 0.63 mg

3) Syrup containing per millilitre:

Compound 9b 25 mg Sorbitol 500 mg Hydroxypropylcellulose 15 mg Glycerol50 mg Methyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 ml Flavour0.05 mg Saccharin natrium 0.5 mg Water ad 1 ml

4) Solution for injection containing per millilitre:

Compound 4a 0.5 mg Sorbitol 5.1 mg Acetic Acid 0.05 mg Saccharin sodium0.5 mg Water ad 1 ml

What is claimed is:
 1. A dihydroindole compound of formula I

wherein A and B are independently O or S; D is a methylene group optionally substituted with one or two C₁₋₄ alkyl groups; Y is a group NR¹ completing a dihydroindole ring, or a group N completing a dihydroindole ring attached via the 1-position; W is a bond, and n+m is 1, 2, 3, 4, 5, or 6; W is CO, SO, or SO₂, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6; or W is O, S, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6, and provided that when Y is N completing a dihydroindole ring attached via the 1-position then m is 2 or 3; and when Y is NR¹ completing a dihydroindole ring linked via the 2-position then m is 1, 2, or 3; R¹ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, aryl, heteroaryl, aryl-C₁₋₆ alkyl, heteroaryl-C₁₋₆ alkyl, acyl, thioacyl, C₁₋₆ alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl or heteroarylsulfonyl, or R¹⁵VCO— wherein V is O or S and R¹⁵ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl, or a group R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— wherein R¹⁶ and R¹⁷ are independently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl, or R¹⁶ and R¹⁷ together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepin group; R²-R⁵ are independently selected from hydrogen, halogen, cyano, nitro, C₁₋₆ alk(en/yn)yl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxy, C₃₋₈ cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, C₁₋₆ alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C₁₆ alkylsulfonyl, one of R²-R⁵ alternatively being a group —NR¹³R¹⁴ wherein R¹³ is selected from the R¹ substituents; R¹⁴ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆alk(en/yn)yl, aryl, heteroaryl, aryl-C₁₋₆ alkyl or heteroaryl-C₁₋₆alkyl, or R¹³ and R¹⁴ together with the N-atom to which they are linked form a group

wherein Q is C═O, C═S or CH₂; T is NH, S, O or CH₂; and p is 1-4 inclusive; R⁶-R⁸ are independently selected from hydrogen, halogen, cyano, nitro, C₁₋₆-alk(en/yn)yl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl or C₁₋₆ alkylsulfonyl; wherein any of the aryl groups or aryl moieties is selected from the group consisting of phenyl and napthyl, and any of the heteroaryl groups or heteroaryl moieties is selected from the group consisting of indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl; or a pharmaceutically acceptable acid addition salt thereof.
 2. A compound of claim 1, wherein Y is NR¹ and the resulting dihydroindole ring is linked to the W—(CH₂)_(n) group via the 1- or 3-position.
 3. A compound of claim 2, wherein R¹ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkylcarbonyl.
 4. A compound of claim 1, wherein A and B are both O.
 5. A compound of claim 1, wherein D is methylene or methylene substituted with one or two methyl groups.
 6. A compound of claim 1, wherein W is a bond and n+m is 1, 2, 3 or
 4. 7. A compound of claim 6, wherein n+m is 1 or
 2. 8. A compound of claim 1, wherein none of R²-R⁵ is a group NR¹³R¹⁴.
 9. A compound of claim 1, wherein each of R²-R⁵ is selected from the group consisting of hydrogen, halogen or cyano.
 10. A compound of claim 1, wherein at least one of R²-R⁵ is a group NR¹³R¹⁴.
 11. A compound of claim 1, wherein R¹³ is acyl, C₁₋₆ alkyl C₁₋₆alkoxy or a group R¹⁶R¹⁷NCO— wherein R¹⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, cycloalkyl-C₁₋₆alkyl, aryl or heteroaryl and R¹⁷ is hydrogen or C₁₋₆ alkyl, and R¹⁴ is hydrogen or lower alkyl.
 12. A compound of claim 11, wherein R¹³ is formyl, acetyl, methylaminocarbonyl, methylaminothiocarbonyl, dimethylaminocarbonyl, dimethylaminothiocarbonyl, methylsulfonyl, aminocarbonyl, cyclopropylcarbonyl, methyl, pyrrolidinylcarbonyl or 4-fluorophenylaminocarbonyl.
 13. A compound of claim 10, wherein R¹³ and R¹⁴ are linked together to form a 5-7 membered unsubstituted lactam ring or a pyrrolidinyl, piperidinyl or perhydroazepin group.
 14. A compound of claim 2, wherein Y is NR¹, the dihydroindole ring is linked via the 3- or 2-position, A and B are both O, and D is optionally substituted methylene.
 15. A compound of claim 14, wherein W is a bond.
 16. A compound of claim 14, wherein n+m is 1 or 2, and R¹-R⁵are all hydrogen.
 17. A compound of claim 1, which is selected from the group consisting of: 2,3-Dihydro-3-[4-[4-[3,4-methylendioxyphenyl)piperazine-1-yl]butyl-1-oxo]]-1H-indole; or 1-Acetyl-2,3-dihydro-3[2-[4-[(3,4-methylendioxyphenyl)piperazine-1-yl]ethyl]]-1H-indole.
 18. A method of treating positive and negative symptoms of schizophrenia and other psychoses, said method comprising administering a pharmaceutically effective amount of the compound of claim
 1. 19. A pharmaceutical composition comprising a compound of claim 1 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents. 